Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][O:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1.COCCO[AlH2-]OCCOC.[Na+].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][O:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[CH2:24][OH:25])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1OCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccccc1OCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
In a flask placed under an argon flow, 0.16 g (0.352 mmol) of methyl 2-((3-((3-(trifluoromethyl)-phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were dissolved in 4 ml of tetrahydrofurane with magnetic stirring, the mixture was cooled to 0° C. and then 0.148 ml (0.492 mmol) of RED-Al were added. The mixture was stirred at 0° C. for 15 min before being diluted with 15 ml of ethyl acetate and poured into 20 ml of water. With intense stirring, 1 ml of a NaOH aqueous solution (32% by mass) was slowly added. After separation, the organic phase was washed with 2×10 ml of water. The aqueous phases were extracted with 2×5 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by trituration in 10 ml of diisopropyl ether. The solid was isolated by filtration and dried in vacuo. 0.091 g (yield=58%) of (2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)phenyl)methanol were obtained as a pale brown solid. LC-MS: m/z=425 (M+2H+); UV purity at 254 nm=94%. 1H NMR (300 MHz, DMSO) δ 8.77 (d, J=6.8 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.73 (dt, J=14.3, 7.8 Hz, 3H), 7.55-7.43 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.20 (d, J=3.6 Hz, 3H), 7.03-6.86 (m, 1H), 5.39 (s, 2H), 4.98 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1.[OH:19][CH:20]([CH2:27][OH:28])[CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[H-].[Na+]>>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH:20]([OH:19])[CH2:27][OH:28])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC(O)Cc1ncc[nH]1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2ccccc2)c1
Yield: 63.6 %

Procedure:
Using benzyl 3-(3-iodopropyl)phenyl ether (1.98 g), 2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride (0.259 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (1.31 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][OH:2].[OH-].[K+].Cl[C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=2[N:10]=1>CO>[OH:2][NH:1][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: NO
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: ONc1nc2ccc(C(F)(F)F)cc2s1
Temperature: 20 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
0.88 g of hydroxylamine hydrochloide is added to a solution of 0.7 g of potassium hydroxide in 15 ml of methanol and the reaction mixture is brought to reflux for 10 minutes. 0.5 g of 2-chloro-6-(trifluoromethyl)benzothiazole is then added and reflux is continued for 8 hours. After cooling to a temperature in the region of 20° C., the insoluble material is filtered off, the filtrate concentrated to dryness and the residue taken up in dichloromethane. The organic phase is washed with water and then dried and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa). The crude product thus obtained is purified by flash chromatography on a silica column, an ethyl acetate/cyclohexane (40/60 by volume) mixture being used as eluent. 0.35 g of 2-hydroxyamino-6-(trifluoromethyl)benzothiazole is thus obtained in the form of an orangey powder, the melting point of which is greater than 260° C. (Analysis % calculated C: 41.03, H: 2.15, N: 11.96, S: 13.69; found C: 41.4, H: 1.6, N: 12.3, S: 13.9) [1H N.M.R. spectrum (200 MHz, d6-(CD3)2SO, δ in ppm): 7.2 (broad s, 1H, aromatic CH), 7.53 (d, J=7 Hz, aromatic CH, 8.0 (broad s, 1H, aromatic CH), 10.07 (s, 1H, NH, 11.05 (s, 1H, OH)].
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:45](NC1C=CC(C(O)=O)=CC=1)=[O:46]>>[CH3:45][O:46][CH2:8][CH2:9][NH:10][C:33]([CH:31]1[CH2:32][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)[CH2:30]1)=[O:35]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Product: COCCNC(=O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 2-methoxyeth-1-ylamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 8.05 (t, J=5.5 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.42-6.34 (m, 2H), 4.79-4.73 (m, 4H), 3.93-3.86 (m, 2H), 3.73 (t, J=6.6 Hz, 2H), 3.52-3.41 (m, 1H), 3.38-3.30 (m, 2H), 3.27-3.21 (m, 5H); MS (ESI(+)) m/e 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:14]([C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[N:12][C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)cnc1NC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 130 °C

Procedure:
To a mixture of ethyl 2-amino-5-chloronicotinate (143, Example 18) (344.9 mg, 1.719 mmol) in pyridine (2.0 mL, distilled) in a 10 mL round-bottom flask with stirring was added a solution of 3-phenoxyphenylacetyl chloride (812.5 mg, 3.293 mmol) in dry CH2Cl2 (2.0 mL). The mixture was gradually heated to reflux (130° C., oil bath), over which time the CH2Cl2 was allowed to evaporate. The resulting solution was refluxed for 3.5 h, then cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were washed with water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving a dark green liquid. This liquid was chromatographed on silica gel (24 g, Mallinckrodt, grade 62, mesh 60-200) and eluted with hexanes-EtOAc (1:4, 250 mL). The desired fractions were collected (Rf =0.83) and rota-evaporated to dryness, leaving a green oil. This oil eventually precipitated out as a wet green mass. Crystallization from ethanol afforded the title compound as a light brown flakes, 114 mg (16.1%), mp 103°-4° C.; 1H NMR (CDCl3): δ1.39 (t, J=7.2, 3, CH3CH2), 3.88 (s, 2, benzylic), 4.35 (q, J=7.2, 2, CH3CH2O), 7.10 (m, 9, phenyl), 8.24 (d, J=2.4, 1, py), 8.52 (d, J=2.4, 1, py), 10.70 (d, J=2.4, 1, NH); IR (KBr): 3434, 3155, 2925, 1722, 1659, 1401, 1252, 1205, 1102, 775, 700; HPLC: 99%; LRMS: 410 (M+, 40), 211 (35), 210 (100), 200 (35), 183 (30), 181 (40), 128 (15), 89 (50), 77 (20), 51 (15); HRMS Calcd: 410. 1033. Found: 410.1026.
Reaction SMILES: [S:1](Cl)([O:4][CH2:5]OS(Cl)(=O)=O)(=[O:3])=[O:2].[NH+]1C=CC=C[CH:13]=1.[CH3:18][S:19]([O-:22])(=[O:21])=[O:20]>C(=O)(OC)OC>[CH3:18][S:19]([O:22][CH2:5][O:4][S:1]([CH3:13])(=[O:3])=[O:2])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)OCOS(=O)(=O)Cl
Reactant: CS(=O)(=O)[O-]
Reactant: c1cc[nH+]cc1
Solvent: COC(=O)OC
Product: CS(=O)(=O)OCOS(C)(=O)=O

Procedure:
In dimethyl carbonate (10 mL), methylene bis(chlorosulfate) [CISO2OCH2OSO2Cl] (1.5 g, 6.1 mmol) synthesized on the basis of the method described in U.S. Pat. No. 4,649,209 was reacted with methanesulfonic acid pyridinium salt (2.1 g, 12.0 mmol) under agitation at 55° C. for 3 hours. After the reaction was completed, precipitated chlorosulfonic acid pyridinium salt was separated through filtration, and concentration was performed under reduced pressure, so as to obtain a light brown solid. An adsorption treatment with activated carbon was performed and, thereafter, refining was performed through recrystallization, so as to obtain a desired product, methylene bis(methanesulfonate), at a yield of 48% (0.6 g, 2.9 mmol). The measurement result of 1H NMR is as described below.
Reaction SMILES: Br[C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20].[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.N1C=CC=CC=1C1C=CC=CN=1>CC(N(C)C)=O.[Cu].O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=2[S:16]([OH:19])(=[O:18])=[O:17])=[CH:24][CH:23]=1.[Na:20]
Reactant: Brc1ccc(I)cc1
Reactant: O=S(=O)(O)c1cc(S(=O)(=O)O)c(Br)c(S(=O)(=O)O)c1
Agent: [Cu]
Agent: [Na]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c(-c2ccc(Br)cc2)c(S(=O)(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of 2-bromo-benzene-1,3,5-trisulfonic acid, sodium salt and 1-bromo-4-iodo-benzene (1 equivalent) in DMAc can be treated with activated copper bronze (2.2 equivalents) and 2,2′-bipyridine (0.2 equivalents) then heated to 80° C. for 4 hours. The cooled mixture can be poured into water, the solids filtered off, and the filtrate evaporated and then dried under vacuum. The crude product can be isolated by extracting the solids with moist ethanol, filtering off the solids, and evaporating the filtrate to give 4′-bromo-biphenyl-2,4,6-trisulfonic acid, sodium salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4F)cc23)CC1
Yield: 79.4 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.4 μL (0.0458 mMol) 2-fluorobenzoyl chloride, 12.2 mg (80%) of the title compound were recovered.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[OH:1][CH:2]1[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:3]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CC1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C(c2ccccc2)C1
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
To a solution of benzyl 3-oxo-4-phenylpyrrolidine-1-carboxylate (200 mg, 0.0007 mol) in tetrahydrofuran (2.0 mL, 0.025 mol) under a N2 atmosphere at −78° C. was added L-Selectride® in tetrahydrofuran (1M, 4.1 mL) with stirring. The mixture was stifled at this temperature for 1.5 hours. LCMS indicated that the starting material was consumed and the reaction was quenched with water. The solution was adjusted to pH ˜6 to 7 and was extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The resulting residue was purified with Combiflash, eluting with EtOAc/hexane to afford the product (125 mg). LCMS: m/z 298.0 (M+H+); 320.0 (M+Na+).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([C:23]1[CH:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:24]=1)[C:12]([NH:14][C@H:15]1[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]1=[O:22])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH:26]=[CH:27][C:23]([C@@H:11]([C:12]([NH:14][C@H:15]4[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]4=[O:22])=[O:13])[CH2:10][C:9]([OH:42])=[O:8])=[CH:24]3)=[CH:33][CH:32]=2)=[CH:35][CH:36]=1)#[N:41]
Reactant: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 81 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc for 3 h to give a 81% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid: 1HNMR (DMSO-d6): δ 12.2 (bs, 1H), 8.48 (d, 1H, J=8.8 Hz), 7.92 (s, 4H), 7.86 (d, 2H, J=8.5 Hz), 7.67 (d, 2H, J=8.5 Hz), 7.40 (s, 1H), 7.37 (s, 1H), 6.33 (s, 1H), 4.75 (d, 1H, J=8.8 Hz), 4.08, 4.00 (AB quartet, 2H, J=8.6 Hz), 3.97-3.92 (m, 1H), 3.01-2.92 (m, 1H), 2.64 (dd, 1H, J=16.54, 4.0 Hz), 1.05 (s, 3H), 0.97 (s, 3H); Anal. Calculated for C27H25N3O5•C5H12O (MTBE): C, 68.67; H, 6.66; N, 7.51. Found: 69.00, 68.91; H, 6.37, 6.42; N, 7.60, 7.52.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])C.[NH3:36].CO>>[C:4]([CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(=[O:3])[NH2:36]
Reactant: N
Reactant: CCOC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: CO
Product: NC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a sealed tube, a solution of [4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-acetic acid ethyl ester (40 mg, 0.08 mmol) in a 7 N solution of ammonia in methanol (345 μL, 2.41 mmol) was warmed at 100° C. After 6 hours, the mixture was cooled to room temperature, and the resulting precipitate collected by filtration. The solid was purified by reversed-phase HPLC (C18 column, flow rate=25 mL/minute) using a 20 minute gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA). Desired fractions from the column were combined and neutralized with saturated aqueous sodium bicarbonate, concentrated and extracted with a 10% solution of methanol in dichloromethane (3×30 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated. The solid was triturated with methanol (3×1 mL), filtered and dried to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2([CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].O1CCOCC1>CO>[ClH:24].[ClH:24].[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:22][CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(CN2CCC3(CC2)CNC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 7-benzyl-2,7-diazaspiro[3.5]nonane-2-carboxylate (CAS 929301-99-5 WO2007030061) in methanol was added 4 N HCl/dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to obtain the title compound. MS (DCI+) m/z 217 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[C:15](=[CH:22][OH:23])[CH2:16]1)[CH2:11][CH2:10]3.N1[CH:30]=[CH:29]C=CC=1.[OH2:31]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[C:15](=[CH:22][O:23][C:29](=[O:31])[CH3:30])[CH2:16]1)[CH2:11][CH2:10]3
Reactant: O
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(=CO)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(=COC(C)=O)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
A mixture of 17β-methoxy-2-hydroxymethylen-5α-androstan-3-one (U.S. Pat. No. 3,980,638, Example 3, 0.5 gm.) in acetic anhydride (3.0 ml.) and pyridine (3 ml.) is allowed to stand at 20°-25° for 24 hours. The reaction mixture is then poured into water and the product separates. The product is collected and dissolved in benzene and purified by column chromatography on Florisil. The appropriate fractions (TLC) are pooled and concentrated to give a residue. The residue is crystallized from methanol to give 17β-methoxy-2-acetoxymethylen-5α-androstan-3-one.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[C:15]([CH2:17][C:18]([NH2:20])=[S:19])#[N:16]>>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:20]=[C:18]([CH2:17][C:15]#[N:16])[S:19][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: N#CCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 48 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (2.4 g, 48% yield), and it was carried through without further purification. MS (ESI) m/z: Calculated for C12H7F3N2S: 268.03. found: 269.0 (M+H)+.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:42].C(N(C(C)C)C(C)C)C.F[C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:59]#[N:60]>CN(C)C=O.C1COCC1>[C:59]([C:58]1[CH:61]=[CH:62][C:63]([N:64]2[CH2:69][CH2:68][N:67]([C:11]([C:10]3[CH:14]=[C:15]([S:18]([NH2:19])(=[O:20])=[O:21])[CH:16]=[CH:17][C:9]=3[OH:8])=[O:13])[CH2:66][CH2:65]2)=[CH:56][C:57]=1[F:42])#[N:60]
Reactant: COc1ccc(COc2ccc(S(N)(=O)=O)cc2C(=O)O)cc1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: F[B-](F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3O)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid in 4 ml dimethylformamide and 12 ml THF were added 5.3 mmol TBTU, 17.5 mmol N-ethyldiisopropylamine and 3.5 mmol 3-fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). The reaction was then stirred at RT for 1 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 525.1 (M+H+)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([CH3:12])[N:11]=2)[N:8]=1)[CH3:2].Cl[S:14]([OH:17])(=O)=[O:15].C([N:20](CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCCl.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([S:14]([NH2:20])(=[O:17])=[O:15])=[C:10]([CH3:12])[N:11]=2)[N:8]=1)[CH3:2]
Reactant: CCc1ccc2nc(C)cn2n1
Reactant: O=S(=O)(O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc2nc(C)c(S(N)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
6-Ethyl-2-methylimidazo[1,2-b]pyridazine (2.70 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (30 ml), and chlorosulfonic acid (1.27 g, 18.5 mmol) was added thereto under stirring at room temperature, and the mixture was stirred for 5 hours under reflux. Then, the reaction solution was cooled to about 70° C., and triethylamine (2.38 g, 23.5 mmol) was added dropwise thereto over 1 minute. After dropping, the reaction solution was stirred for 20 minutes under reflux. Thereafter, the reaction solution was cooled to about 70° C., and phosphorus oxychloride (3.86 g, 25.2 mmol) was added dropwise thereto over 1 minute. After dropping, the mixture was stirred for 2 hours under reflux. The reaction solution was left and cooled to about 50° C., and poured into 50 ml warm water (about 50° C.). The mixture was stirred for 5 minutes, and the organic layer was separated. The aqueous layer was extracted with chloroform (50 ml×2). The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated. The residues were dissolved in acetonitrile (40 ml), and 14 N ammonia water (7 ml) was added thereto under stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured onto iced water (150 ml) and adjusted to about pH 4 with conc. hydrochloric acid, to form crystals which were then collected by filtration, washed with water and dried under reduced pressure. Thereafter, the crystals were purified by silica gel column chromatography (chloroform:acetone=9:1→4:1). The title compound was obtained as white crystals. The yield was 1.8 g (44.7%).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:10]=[C:11]([C:19]2[C:20]([CH3:34])=[CH:21][C:22]([O:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[N:23][CH:24]=2)[CH:12]=[CH:13][C:14]=1[C:15](=[NH:18])[NH:16]O>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:15]([C:14]1[CH:13]=[CH:12][C:11]([C:19]2[C:20]([CH3:34])=[CH:21][C:22]([O:25][CH2:26][C:27]([CH3:32])([CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[N:23][CH:24]=2)=[CH:10][C:9]=1[F:8])(=[NH:16])[NH2:18]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)NO)c(F)c2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)N)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Acetic anhydride (1.62 mL) was added to an acetic acid (10 mL) solution containing methyl 3-({5-[3-fluoro-4-(N-hydroxycarbamimidoyl)phenyl]-4-methylpyridin-2-yl}-oxy)-2,2-dimethylpropanoate (3.65 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), 10% palladium carbon (50%, 365 mg) was added to the resulting solution, and the mixture was stirred under hydrogen atmosphere at room temperature for 13 hours. The catalyst was filtered off by using a membrane filter, and the filtrate was concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration, washed with ether and dried to obtain methyl 3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acetic acid salt (2.45 g).